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Intro to Drug Absorption
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Intro to Drug Absorption
Welcome to the first lesson in our Pharmacokinetics & Drug Metabolism course! Today, we'll delve into the foundational concept of drug absorption. Absorption is the process by which an un-ionized drug moves from its site of administration to the systemic circulation (bloodstream). This is a critical step in determining the onset, intensity, and duration of a drug's pharmacological effect, as only absorbed drug can reach its target site. The route of administration significantly influences the absorption process. For instance, intravenous (IV) administration bypasses absorption entirely, delivering the drug directly into the bloodstream, thus exhibiting 100% bioavailability. In contrast, oral administration requires the drug to navigate various physiological barriers, such as the gastrointestinal (GI) tract, before reaching systemic circulation. Key factors affecting drug absorption include the physicochemical properties of the drug (e.g., lipophilicity, molecular size, pKa), the formulation (e.g., tablets, capsules, solutions), and physiological factors at the absorption site (e.g., pH, surface area, blood flow, presence of food, gastric emptying rate).
Mechanisms of Drug Absorption
Drugs primarily cross biological membranes via several mechanisms, each with varying efficiencies and specificities: Passive Diffusion: This is the most common mechanism for the vast majority of drugs. It involves the movement of a drug from an area of high concentration to an area of low concentration, down its concentration gradient, without the expenditure of metabolic energy. The drug must be sufficiently lipophilic and un-ionized to readily traverse the lipid bilayer of cell membranes. Facilitated Diffusion: This process also occurs down a concentration gradient but requires the assistance of a membrane protein (carrier). It does not require metabolic energy but is saturable and can be inhibited by competitive molecules. Active Transport: This mechanism involves the movement of drugs against their concentration gradient, requiring both a carrier protein and the expenditure of metabolic energy (e.g., ATP hydrolysis). It is saturable, specific, and can be inhibited. Examples include P-glycoprotein efflux pumps, which can actively transport drugs out of cells. Endocytosis (Pinocytosis/Phagocytosis): This involves the engulfment of drugs by the cell membrane, forming vesicles that internalize the drug. This mechanism is typically less significant for most small-molecule drugs but can be important for large molecules like proteins or nanoparticles. The extent of ionization plays a crucial role in passive diffusion. Weak acids and weak bases are the most common drug types. According to the Henderson-Hasselbalch equation, the ratio of ionized to un-ionized drug depends on the drug's pKa and the pH of the environment. Only the un-ionized form is generally sufficiently lipophilic to passively diffuse across lipid membranes. For a weak acid (HA): pH = pKa + log([A-]/[HA]) Where [HA] is the un-ionized form and [A-] is the ionized form. For a weak base (B): pH = pKa + log([B]/[BH+]) Where [B] is the un-ionized form and [BH+] is the ionized form. Consider a weak acid with a pKa of 3.0. In the stomach (pH ~1.5), a significant fraction of the drug will be in its un-ionized form (HA), favoring absorption. In the small intestine (pH ~6.5), it will be predominantly ionized (A-), hindering passive diffusion. The surface area and blood flow at the absorption site are also critical. The small intestine, with its vast surface area due to villi and microvilli, and rich blood supply, is the primary site for absorption of most orally administered drugs, even if they are largely ionized at intestinal pH. This physiological advantage often outweighs the pH-partitioning effect. Let's consider a practical example. If we administer a drug orally, its journey involves: Disintegration (for solid dosage forms) Dissolution (drug dissolves in GI fluids) Movement across the GI membrane (absorption) Entry into the portal circulation Passage through the liver (first-pass metabolism, if applicable) Entry into systemic circulation This sequence highlights why oral bioavailability can be significantly less than 100%.
Key Takeaways
Drug absorption is the movement of a drug from its administration site into systemic circulation. Routes of administration profoundly impact absorption characteristics and bioavailability. Passive diffusion is the most common absorption mechanism, favored by un-ionized, lipophilic drugs. The Henderson-Hasselbalch equation helps predict ionization state based on pH and pKa. Physiological factors like surface area, blood flow, and gastric emptying rate are crucial determinants of absorption. First-pass metabolism can significantly reduce the amount of drug reaching systemic circulation after oral administration.
Practice Exercise
A new drug candidate is a weak base with a pKa of 8.0. You are tasked with predicting its absorption characteristics in the stomach (pH ~1.5) versus the small intestine (pH ~6.5). Explain, using the Henderson-Hasselbalch equation, in which environment the drug would be predominantly un-ionized and thus more readily absorbed via passive diffusion. What other physiological factors might influence its overall absorption from the GI tract, and how?
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